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Two-step activation prodrugs: transplatin mediated binding of chemotherapeutic agents to vitamin B-12


Tran, Mai Thanh Quynh; Furger, Evelyne; Alberto, Roger (2013). Two-step activation prodrugs: transplatin mediated binding of chemotherapeutic agents to vitamin B-12. Organic & Biomolecular Chemistry, 11(19):3247-3254.

Abstract

Clinically approved organic chemotherapeutic drugs such as cytarabine, dacarbazine and anastrozole were attached to B12via a {CN-trans-Pt(NH3)2}-bridge to yield [{Co}-CN-{trans-Pt(NH3)2}-{drug}](2+). The active organic drugs are protected by the platinum complex and by B12, which represents at the same time the targeting vector. We refer to these bioconjugates as two-step activation prodrugs since two reactions are finally required to liberate the actual organic drugs. All three prodrugs are soluble and stable in water. The physiological stability and the therapeutic efficiency of [{Co}-CN-{trans-Pt(NH3)2}-{cytarabine}](2+) (2) were studied. Under physiological conditions, 2 is stable for 3 days. Its affinity to the cobalamin transport proteins (haptocorrin, intrinsic factor and transcobalamin) is not substantially affected despite the introduction of a bulky group in the β-axial position. The cleavage of the [trans-CN-Pt(NH3)2-{cytarabine}](+) complex was observed upon chemical reduction of Co(III)→ Co(II) with Zn(0). Cytarabine was subsequently released from the cleaved complex to exhibit its cytotoxicity. 2 displayed a reduced cytotoxicity (IC50 = 230 ± 62 nM) as compared to cytarabine (IC50 = 30 ± 5 nM). However, cytarabine released from 2 showed comparable cytotoxicity (IC50 = 30 ± 11 nM).

Abstract

Clinically approved organic chemotherapeutic drugs such as cytarabine, dacarbazine and anastrozole were attached to B12via a {CN-trans-Pt(NH3)2}-bridge to yield [{Co}-CN-{trans-Pt(NH3)2}-{drug}](2+). The active organic drugs are protected by the platinum complex and by B12, which represents at the same time the targeting vector. We refer to these bioconjugates as two-step activation prodrugs since two reactions are finally required to liberate the actual organic drugs. All three prodrugs are soluble and stable in water. The physiological stability and the therapeutic efficiency of [{Co}-CN-{trans-Pt(NH3)2}-{cytarabine}](2+) (2) were studied. Under physiological conditions, 2 is stable for 3 days. Its affinity to the cobalamin transport proteins (haptocorrin, intrinsic factor and transcobalamin) is not substantially affected despite the introduction of a bulky group in the β-axial position. The cleavage of the [trans-CN-Pt(NH3)2-{cytarabine}](+) complex was observed upon chemical reduction of Co(III)→ Co(II) with Zn(0). Cytarabine was subsequently released from the cleaved complex to exhibit its cytotoxicity. 2 displayed a reduced cytotoxicity (IC50 = 230 ± 62 nM) as compared to cytarabine (IC50 = 30 ± 5 nM). However, cytarabine released from 2 showed comparable cytotoxicity (IC50 = 30 ± 11 nM).

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2013
Deposited On:18 Oct 2013 10:59
Last Modified:05 Apr 2016 17:02
Publisher:RSC Publishing
ISSN:1477-0520
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1039/C3OB40093J
PubMed ID:23584074

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